Sickle cell anemia is an autosomal recessive disorder and the most common genetic disease affecting African Americans. Approximately 0.15 percent of African Americans are homozygous for sickle cell disease, and 8 percent have sickle cell trait. Acute pain crisis and acute chest syndrome (ACS) are common complications of sickle cell anemia. Inhaled nitric oxide (NO) has been proposed as a possible therapy for ACS. Anecdotally, NO has been described to rapidly improve the hypoxemia and the clinical course of ACS. Furthermore, a number of recent studies have suggested that NO may have a favorable impact on sickle hemoglobin at the molecular level and could improve the abnormal microvascular perfusion that is characteristic of sickle cell anemia. This clinical trial was designed to evaluate the physiologic and molecular effects of inhaled NO and a currently available, safe, FDA-approved medication, nitroglycerin, that is a nitric oxide donor (i.e., a source of NO after metabolism in the body), in study subjects with and without sickle cell anemia. Whole blood was analyzed to characterize the metabolism of NO and NO donors, the molecular interactions between hemoglobin and NO, the duration of effect of these therapies on hemoglobin oxygen affinity and other properties of the erythrocyte and intracellular hemoglobin (including the solubility of deoxy sickle hemoglobin).We found that during NO inhalation at 80 ppm, NO binds to the heme of hemoglobin and is delivered to the peripheral circulation. The amount delivered is sufficient to restore regional blood flow to the forearm during NO synthase inhibition (measured by strain-gauge plethysmography). This may prove an effective therapy to increase regional blood flow during sickle cell pain crisis and after vascular procedures such as angioplasty. We also characterized the effect of NO delivery on microvascular perfusion in study subjects with and without sickle cell anemia by magnetic resonance imaging (MRI) of lower extremity skeletal muscle enhancement during first passage of intravenously injected gadolinium contrast. Perfusion measurements were paired with 31-phosphorus magnetic resonance spectroscopy (31-P-MRS) study of the concentration of muscle high-energy phosphate compounds. We were unable to appreciate changes in blood flow in our pilot study using this imaging modality. This ongoing project will allow three major assessments: (1) the characterization of the microvascular perfusion at rest and during exercise in study subjects with sickle cell anemia, (2) the effects of NO on red cell and hemoglobin function and skeletal muscle perfusion in normal study subjects (without sickle cell anemia), and finally, (3) the effects of NO on red cell and hemoglobin function and skeletal muscle perfusion in study subjects with sickle cell anemia. Our hypothesis is that one or more of these effects could be of potential therapeutic benefit to sickle cell anemia patients.